Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk
Authors: Mahmoud I. Abdel-Aziz, Jonathan Thorsen, Simone Hashimoto, Susanne J. H. Vijverberg, Anne H. Neerincx, Paul Brinkman, Wim van Aalderen, Jakob Stokholm, Morten Arendt Rasmussen, Michael Roggenbuck-Wedemeyer, Nadja H. Vissing, Martin Steen Mortensen, Asker Daniel Brejnrod, Louise J. Fleming, Clare S. Murray, Stephen J. Fowler, Urs Frey, Andrew Bush, Florian Singer, Gunilla Hedlin, Björn Nordlund, Dominick E. Shaw, Kian Fan Chung, Ian M. Adcock, Ratko Djukanovic, Charles Auffray, Aruna T. Bansal, Ana R. Sousa, Scott S. Wagers, Bo Lund Chawes, Klaus Bønnelykke, Søren Johannes Sørensen, Aletta D. Kraneveld, Peter J. Sterk, Graham Roberts, Hans Bisgaard, Anke H. Maitland-van der Zee, Johan Kolmert, Anna James, Ana R. Sousa, John H. Riley, Stewart Bates, Per S. Bakke, Massimo Caruso, Pascal Chanez, Stephen J. Fowler, Thomas Geiser, Peter Howarth, Ildiko Horvath, Norbert Krug, Paolo Montuschi, Marek Sanak, Annelie Behndig, Dominick E. Shaw, Richard G. Knowles, Cecile T. J. Holweg, Asa M. Wheelock, Barbro Dahlen, Kjell Alving, Kian Fan Chung, Ian M. Adcock, Peter J. Sterk, Ratko Djukanovic, Sven-Erik Dahlen, Craig E. Wheelock, Lars Andersson, Charles Auffray, Hans Bisgaard, Bertrand De Meulder, Louise J. Fleming, Urs Frey, Rene Lutter, Sharon Mumby, Graham Roberts, M. Uddin, S. S. Wagers, N. Zounemat Kermani
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis β-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-β (transforming growth factor-β) (highest in the Veillonella cluster) and Wnt/β-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.